Doxorubicin is a known anthracycline antibiotic described, e.g., in U.S. Pat. No. 3,590,028. Doxorubicin, and the closely related compound daunomycin, are antineoplastic agents of established clinical utility. Doxorubicin hydrochloride, available from Adria Laboratories, Inc. under the trade name Adriamycin.RTM., has been approved by the Food and Drug Administration for use in clinical research, and is one of the most powerful anti-cancer drugs available against numerous forms of cancer.
At present, doxorubician is produced commercially from a soil fungus by a fermentation process. A suitable fermentation technique for preparing doxorubicin is described in U.S. Pat. No. 3,590,028. Such techniques are inherently expensive and limit the types of molecules that can be produced. Because of the inherent disadvantages of presently available commercial techniques for producing doxorubicin and such related compounds as daunomycin, substantial effort has been devoted to developing processes for producing such compounds by chemical synthesis.
Doxorubicin consists of an aglycone, adriamycinone, and an amino sugar, daunosamine. Similarly, daunomycin consists of the aglycone daunomycinone, and the amino sugar, daunosamine. Specifically, doxorubician and daunomycin have the formula: ##STR1## with the compound being doxorubicin when R is --OH and daunomycin when R is --H.
Techniques for synthesizing doxorubicin and daunomycin, and their aglycones, adriamycinone and daunomycinone, are known. See, e.g., Wong et al., Canadian Journal of Chemistry, Vol. 51, p. 466 (1973); Acton et al., Journal of Medicinal Chemistry, Vol, 17, No. 6, p. 659 (1974); Kende et al., Journal of American Chemical Society, Vol. 97, No. 15, p. 4425 (1975) and Vol. 98, No. 7, p. 1967 (1976); and Kende et al, U.S. Pat. No. 4,021,457. Techniques for attaching daunosamine to the aglycones are also known. See, e.g., Acton et al., supra, and Smith et al., Journal of American Chemical Society, Vol. 98, No. 7, p. 1969 (1976).
None of the known techniques for the synthesis of anthracycline antibiotics such as doxorubicin has proven to be commercially successful. Because of the demand for, and scarcity of, these compounds, a commercially practical technique for synthesizing them is greatly needed. Since the sugar daunosamine provides an important part of these compounds, and since it is known both how to synthesize the aglycones adriamycinone and daunomycinone, as well as how to attach daunosamine to the aglycones, techniques for synthesizing daunosamine, and related compounds, are highly desirable as part of a technique for the total synthesis of the anthracycline antibiotics.
While techniques for synthesizing daunosamine are known, the known techniques suffer severe shortcomings that limit their practical utility. For example, the process disclosed in Marsh et al., Chemical Communications, p. 973 (1967) uses a difficult method to obtain glycal as a starting material and involves the use of a potentially hazardous step of making an azide derivative with sodium azide. Furthermore, in the process disclosed by Marsh et al., isomers are produced that require separation by a difficult chromatographic step. The process disclosed in Horton et al., Carbohydrate Research, Vol. 44, p. 227 (1975), requires the use of a number of very expensive reagents and also results in the production of difficult to separate isomers.
In U.S. Patent Application Ser. No. 908,240, filed May 22, 1978, and which issued as U.S. Pat. No. 4,181,795, a process for synthesizing daunosamine and related compounds, as well as novel intermediates, is disclosed. In U.S. Patent Application Ser. No. 128,298, filed concurrently herewith, disclosed is, inter alia, a process for synthesizing alkyl L-ristosaminides and N-benzoyl-L-ristosamine, ristosamine being a configurational analog of daunosamine.
The present invention provides a practical technique for synthesizing daunosamine hydrochloride. In addition, the present invention provides novel intermediates, and methods for their preparation, valuable in synthesizing daunosamine hydrochloride. Moreover, the synthesis techniques disclosed herein may use, as starting materials, the readily available and inexpensive compounds D-glucose and D-galactose.